Dr Sharon Walmsley
University Health Network, Canada
Romania, January 2012
Prevention, fertility, contraception
and pregnancy
HIV AND WOMEN
Objectives
• To discuss the implications of the recent
prevention trials on HIV transmission to women
• To discuss the alternatives for contraception for
HIV-positive women
• To review means of safe conception for HIV
concordant and serodiscordant couples
• To review the management of pregnancy in the
setting of HIV
Prep trials to prevent transmission with
oral agents in women
• FEM Prep trial of TDF/FTC: trial discontinued due to lack
of efficacy
• VOICE study: oral TDF arm halted due to lack of
efficacy; TDF/FTC arm continues
• Partners Prep study: both TDF and TDF/FTC decreased
transmission in men and women
(62–73% decrease)
• TDF2 trial in young adults in Botswana:
63% reduction in transmission
Baeten et al, Thigpen et al, IAS conference, 2011
Prep for prevention of transmission –
topical treatments
• CAPRISA: 1% tenofovir gel, reduced transmission 39%
overall, 54% in highly adherent women
• VOICE study: 1% tenofovir gel, study discontinued due
to lack of efficacy
• FACTS study: 1% tenofovir gel in young women,
ongoing
• Vaginal rings and gels with other agents
Abdool K Q, et al. Science 2010;329:1168–74.
HPTN 052: HIV-1 transmission
• Early ART, suppressing replication, led to 96% reduction of sexual
HIV-1 transmission in serodiscordant couples
Total HIV-1 Transmission Events: 39
Linked
Transmissions: 28
Delayed
Arm: 27
Immediate
Arm: 1
p < 0.001
Cohen MS, et al. N Engl J Med 2011;365:493–505.
Unlinked or TBD
Transmissions: 11
Based on these findings, the new perinatal
guidelines recommend (AI) initiation of ART for HIVinfected partners in serodiscordant couples wishing
to conceive, if CD4 is <550. Goal: maximal
suppression prior to conception (AIII); consideration
of therapy for CD4 >550 cells (BIII)
PRECONCEPTION
COUNSELING
Preconception counseling
• Should begin at the first visit for any HIV-infected woman
of child-bearing age
– Avoid undesired pregnancy (family planning)
– Avoid potential teratogens (e.g. efavirenz, ribavirin, tobacco,
alcohol, drugs)
– Maximize physical and mental health before pregnancy
– Discuss reproduction options that are safe to partner
– Perform pelvic exam, pap smear, and sexually transmitted
disease screening; treat abnormalities
• Encourage sexual partners to receive HIV testing,
counseling, and care
Ontario fertility study
• Of the 490 HIV+ women, 416 had been pregnant (85%);
56% were UNINTENDED pregnancies
Last Pregnancy being Intended
Ever in Lifetime
No
233
(56%)
Yes
183
(44%)
Loutfy M, et al. HIV Med 2012;13:107–117.
Last Pregnancy being
Intended After HIV
No
106
(54%)
Yes
89
(46%)
Birth control options
Non-hormonal
Progestins
Combination
hormones
Female contraception in HIV-infection
• Hormonal contraception: differ mostly based on the
progesterone component
– Combined contraception (combination estrogen and
progesterone, including pills, injectables, rings, patches)
– Progestins only (injectable: depoprovera or DMPA most
common, “mini pill”, progesterone-containing intrauterine
devices [IUDs])
• Non hormonal contraception
–
–
–
–
Copper IUD
Condom
Diaphragm / cap
Sterilization surgery
DMPA= depo-medroxyprogesterone acetate
ARVs and oral contraceptives:
Drug interactions
ARV Drug
EFV
Effect on
EE* AUC
None
Summary of product characteristics comment
Barrier contraception should always be used in
combination with other methods of contraception
Alternative or additional contraceptive measures are
recommended when co-administered with oestrogenbased contraceptives
NVP, LPV/r, SQV/r,
DRV/r, NFV
ATV/r
19%
Oral contraceptives need to contain >30ug EE
FPV/r
36%
Coadministration with oral contraceptives may increase the
risk of hepatic transaminase elevations, alternative
contraception methods are recommended
MVC
None
Can co-administer with EE
RAL
2%
Can be co-administered without dose adjustment
No data on PK/PD interactions,; what is the impact on ovulation?
*EE=Ethinylestradiol; SmPCs. Available at
http://www.ema.europa.eu (last accessed January 2012).
ACTG 5188: pharmacokinetics of hormonal
contraception when used with LPV/RTV

6-week PK study (oral and transdermal contraception) looking at EE,
Norelgestromin LPV levels in HIV-1 infected women on LPV/r
containing regimens (arm A) compared with women on NRTI-only or
no ARVs (arm B)

Ethinylestradiol was lower (45% in the patch group) and
norelgestromin concentrations higher (83% up in the patch group)

Conclusion: there is a significant interaction with PI-containing ART
regimens. However, due to the increase in progestin level the
contraceptive efficacy of the patch is likely to be maintained.

In that case – use progestins only?
Vogler MA, et al. JAIDS 2010;55:473–82.
Hormonal effects on HIV progression
• Pregnancy: increasing levels of estrogen &
progesterone (late plateau) – no substantial effect on
disease progression
• Hormonal contraception (combined or progestin only)
– Based on animal studies, there is concern regarding adverse
progestin effect on disease progression
– Earlier clinical data conflicting regarding HIV. Increased sexually
transmitted infections
– Important in settings where ART is not available; there is a great
need for safe and effective contraception
Stringer E, et al. AIDS 2009;23:S69–77; Curtis KM, et al. AIDS 2009;23:S55–67.
Safety and tolerability of DMPA
Proportion of subject with HIV RNA levels <400 copies/mL
and median CD4+ cell counts at each sampling
HIV RNA
< 400 Copies/mL
Controla
(n=16)
Nelfinavir
(n=21)
Efavirenz
(n=17)
Nevirapine
(n=16)
Baseline
7/15 (47%)
19/21 (90%)
16/17 (94%)
13/16 (81%)
Week 2
5/14 (36%)
15/21 (71%)
16/17 (94%)
11/13 (85%)
Week 4
7/16 (44%)
12/19 (63%)
16/17 (94%)
14/16 (88%)
Week 8
6/13 (46%)
13/16 (81%)
15/16 (94%)
8/10 (80%)
Week 12
6/15 (40%)
15/17 (88%)
15/16 (94%) 12/12 (100%)
Median CD4+ cell count (cells/µL)
Baseline
704
718
725
620
Week 4
692
620
650
671
Week 12
668
702
774
740
ACTG A5093: Safety and Tolerability of DMPA Among HIV-Infected Women on ART
Watts DH, et al. Contraception 2008;77:84–90.
ACTG A5093: DMPA-related toxicity
(all mild to moderate)
Toxicity
Abnormal bleeding
Headache
Abdominal pain
Anorexia
Fatigue
Insomnia
Mood changes
Body odour changes
Carpal tunnel syndrome
Dizziness
Excess salivation
Low platelet count*
Malaise
Nausea
Vaginal dryness
*Low platelet count=65,000/mm3
Watts DH, et al. Contraception 2008;77:84–90.
Number of women with
event, n (%)
9 (12.9)
3 (4.3)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
2 (2.9)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
1 (1.4)
Effect of DMPA on the pharmacokinatics
of selected PI and NNRTI therapies
• Efficacy of DMPA did not appear to be altered
• DMPA was well-tolerated; side effects were similar to
those reported in HIV-negative women
• Progesterone levels remained low (<1.5ng/mL), with no
presumptive evidence of ovulation through week 12
• Although NVP AUC levels were higher with DMPA, the
increased levels do not appear to be clinically relevant
• DMPA appears to be safe and effective for HIV-infected
women taking NFV, EFV, and NVP-based regimens
ACTG 5093: Effect of DMPA on the PK of Selected PI and NNRTI Therapies
Among HIV-infected Women
Watts DH, et al. Contraception 2008;77:84–90
Hormonal contraception and risk of HIV
acquisition among women in South Africa
Analysis of women in the Carraguard Phase III
efficacy trial:
• 270 of 5567 women (3.7/100wy) became infected
– 2.8/100wy oral contraceptive users
– 4.6/100wy DMPA
– 3.5/100wy Net-En (northisterone enanthate)
– 3.4/100wy in non-hormonal contraceptive group
• Adjusted and non-adjusted rates are not
significantly different
Morrison et al, AIDS 2011; Epub ahead of print,
doi: 10.1097/QAD.0b013e32834fa13d
Effects of injectable hormonal
contraceptives on HIV seroconversion
• 2236 HIV-negative women in Durban, South Africa
• Those reporting using hormonal contraceptives were
less likely to use condoms in their last sexual act
• Hormonal contraceptives increased risk of HIV infection
– adjusted hazard ratio (HR)=1.72 (95% confidence
interval [CI] 1.19–2.49; p=0.005)
Wand H, et al. AIDS 2012;26:375–80.
Hormonal contraception and the risks
of HIV transmission
• 3790 heterosexual serodiscordant couples; in 1314
couples, the HIV seronegative partner was female
• Rates of HIV acquisition
– 6.61/100wy hormonal contraceptive group
– 3.78/100wy in those without
• Adjusted HR=1.98 (95% CI: 1.06–3.68; p=0.03)
• Issue – not the primary endpoint, date on contraceptives
self report, confounders, absolute number of cases small
Heffron R, et al. Lancet Infect Dis 2012;12:19–26.
Contraceptive method and pregnancy
incidence
African women in HIV discordant partnerships:
• Significantly reduced pregnancy incidence in HIV+ and
HIV- women who used injectable contraception
(aHR=0.24; p=0.001)
• Oral contraceptives significantly reduced pregnancy risk
only in HIV seropositive women (aHR=0.51; p=.004)
• Condoms marginally reduced pregnancy incidence
• No pregnancies among women with IUD
Ngure K, et al. AIDS, 2011, Epub ahead of print, doi: 10.1097/QAD.0b013e32834f981c
Increased risk of HIV transmission in
pregnancy in African serodiscordant couples
• Partners in prevention study
• HIV incidence in women
– 7.35 per 100wy during pregnant period
– 3.01 per 100wy during non-pregnant period
• HR=2.34 (95% CI: 1.33–4.09)
• adjusted HR=1.71 (95% CI: 0.93–3.12)
Mugo NR, et al. AIDS 2011;25:1887–95.
General principles for pregnancy
planning
• Take folic acid: 1–5 mg a day for 1–3 months before and
during 1st trimester of pregnancy
• No smoking or drinking
• Maintain a balanced diet
• Terminate the use of recreational drugs
Preconception counseling
• If pregnancy is planned while on ART: attain maximal virologic
suppression prior to pregnancy
• If pregnancy is planned in women not on therapy: obtain
resistance testing and make a decision on choice and timing
of ART
• Prescribe folic acid or prenatal vitamins before conception for
planned pregnancies
• Review diet and avoidance of alcohol, drugs and cigarettes
• Educate about ovulation and fertility (ovulation 101)
Case report: Mrs BK
• 32-year-old HIV-positive woman
• Immigrated from the UK to Canada for
work advancement
• Diagnosed with HIV in 2005, clade A virus
• At diagnosis CD4 210/mm3 and VL 63,000 copies/ml
• Immediately started on efavirenz, abacavir
and lamivudine
Case report: Mrs BK
• Considerable weight gain since diagnosis
• Increased from 70 to 107 kg, mostly centripetal
Case report: Mrs BK
•
•
•
•
Non-smoker
No alcohol or recreational drug use
Immune to hepatitis B after vaccination
Previous LSIL on PAP-, colposcopy normal; no therapy
• Partner HIV-negative; recently married
• Condoms for intercourse
Case report: Mrs BK
• January 2009
• CD4 468 (28%), VL <50/ml
• Decides she wants to become pregnant
How would you advise her?
1. As her viral load is undetectable she is unlikely to
transmit HIV, so can attempt pregnancy with husband
without condoms
2. Use the “turkey baster” approach to impregnation
3. Give her husband PrEP with tenofovir/emtricitabine and
attempt pregnancy
4. Refer to a fertility clinic for consideration of intrauterine
insemination
Prevention of horizontal transmission
• Different clinical scenarios:
– HIV+ woman with HIV- man (serodiscordant) or who
is single or in same sex relationship
– HIV+ man and HIV- woman (serodiscordant)
– HIV+ man and HIV+ woman (seroconcordant)
– HIV+ man who is single, or in same sex relationship,
or a couple seeking egg donation or a surrogate
mother
Different clinical scenarios have different risk of and require
different strategies to prevent horizontal transmission
All scenarios
• Review all different options for insemination
& continuum of risk including:
–
–
–
–
–
–
Unprotected intercourse
Unprotected intercourse with timed ovulation
Home insemination (i.e. turkey baster method)
Intrauterine insemination (IUI) (in fertility clinic)
Sperm washing followed by IUI
Other: in vitro fertilization, intra-cytoplasmic sperm
injection, gestational carrier, adoption
HIV+ woman and HIV- man:
Home insemination
• Inexpensive and simple
• Syringe or turkey baster sucks up semen and is inserted
into the vagina
• Must be inserted deep enough to reach mouth of uterus
• Can be done on the day before and day of ovulation or
every other day (from days 12–17 on a 28-day
period cycle)
• Intrauterine insemination in fertility clinic
HIV+ man and HIV- woman: Sperm
washing and intrauterine insemination
• Sperm Washing:
– process by which sperm is separated
from seminal fluid by centrifugation
– Only seminal fluid carries HIV virus*
– Procedure takes out HIV-free sperm
• Intrauterine Insemination:
– Egg is fertilized inside woman’s body
– “washed sperm” drawn up into a
catheter with a tube small enough to
be inserted into the body
– Delivered directly into uterus
through vagina
– Success rate: 10–20%
*1 case of HIV on sperm
HIV+ man and HIV- woman: Sperm
washing and Intrauterine insemination
• Study involving 1036 serodiscordant couples
(HIV+ male, HIV- female) wishing to procreate
• Results:
– No transmission of HIV to female partner observed
after 3272 cycles with complete follow-up information
– Pregnancy resulted in 580 / 3315 cycles where
outcome was known
– Clinical pregnancy rate = 17.5% (per cycle)
Bujan L, et al. AIDS 2007 21:1909–1914.
HIV+ man and HIV- woman:
Unprotected Intercourse
• 62 HIV-serodiscordant couples, in which the
man was positive in 40 cases
• Median VL was <500 at time of conception
• Results
– In all 40 cases, the HIV-seronegative partner
remained uninfected
– One case of vertical transmission
Barreiro P, et al. J Acquir Immune Defic Syndr 2006;43:324–326.
Correlation between plasma viral load
versus semen viral load not perfect
• 5% of 145 HIV-infected men who enrolled in an ART
program with plasma VL undetectable had detectable
HIV-RNA in semen1
• In 25 men who started ART rapidly suppressed virus in
plasma and semen; but when monitored over time, 48%
(12/25) had semen HIV shedding more than once and
16% (4/25) had semen VL > 5,000 copies/mL 2
1. Marcelin AG, et al. AIDS 2008;22:1677–1679;
2. Sheth PM, et al. AIDS 2009;23:2050–4.
Pre-exposure prophylaxis and timed
intercourse for HIV discordant couples
• Male partner VL < 50/ml on cART
• No report of symptoms of current genital infection in
either partner and no unprotected sex with other partners
• Luteinizing hormone (LH) peak to determine optimal time
of conception
(36hr after LH peak)
• PrEP with tenofovir, first dose at LH peak and second
24 hrs later
• 53 situations, no transmission
• Pregnancy rate 26% first attempt, 66% after
five attempts
Vernazza PL, et al, AIDS, 2011, 25: 2005–8.
Both partners are HIV+
• Superinfection: a condition in which a person with
established HIV infection acquires a 2nd strain of
the virus
• Review all different options for insemination and
continuum of risk, including:
–
–
–
–
Unprotected intercourse
Unprotected intercourse with timed ovulation*
Sperm washing with IUI (in fertility clinic)*
Other: IVF, ICSI, sperm donor, adoption
*typically recommended by HCP due to lowest chance of horizontal
transmission; all options after full understanding of risk
PREGNANCY ISSUES
IN HIV
Pregnancy-related issues in HIV
Impact of HIV
on fertility
Impact of HIV
on pregnancy
MTCT
Pregnancyrelated
issues in
HIV
Impact of
pregnancy on
HIV
Diagnosis in
the child
Obstetric
concerns
TESTING
Revised recommendations: Pregnant
women – 1 of 2
• Universal opt-out HIV screening in 1st trimester
– Include HIV in routine panel of prenatal screening tests
– Consent for prenatal care includes HIV testing
– Notification and option to decline
• Second test in 3rd trimester for pregnant women:
– Known to be at risk for HIV
– In jurisdictions with elevated HIV incidence
– In high HIV prevalence health care facilities
Revised recommendations: Pregnant
women – 2 of 2
• Opt-out rapid testing with option to decline for women
with undocumented HIV status in L&D
– Initiate ARV prophylaxis on basis of rapid test result
• Rapid testing of newborn recommended if mother’s
status unknown at delivery
– Initiate ARV prophylaxis within 12 hours of birth on basis of rapid
test result
Why opt-out?
Testing by strategy, USA, 1998–1999
State
Testing Approach
% with HIV
Test
Tennessee
Opt-out
85%
NY
Mandatory NB – non-expedited
Mandatory NB – expedited (48h)
52%
82%
Connecticut
Opt-in
Mandatory NB – expedited (48h)
31%
81%
Maryland
Opt-in
69%
California
Opt-in
39%
Oregon
Opt-in
25%
CDC. MMWR 2002;51:1013–16.
Rapid HIV test: Understanding positive
predictive values
• Test specificity 99.6% (correct 99.6% of the time) testing 1000 patients, 4/1000 will have a false positive
(wrong) result
• HIV prevalence = 10% True positive: 100 (10% of
1000). 4/100 will have a false positive result. Total
positive tests: 104. Positive predictive value: 100/104 =
96% (96% of positives are true positive)
• HIV prevalence = 0.1% True positive: 1 (0.1% of 1000).
4/100 will have a false positive result. Positive predictive
value: 1/5 = 20% (20% of positives are true positive)
Positive predictive value: Depends on
specificity and varies with prevalence
HIV prevalence
Oraquick PPV
Specificity 99.9%
EIA PPV (blood)
Specificity 99.8%
10%
99%
98%
5%
98%
96%
2%
95%
91%
1%
91%
83%
0.5%
83%
71%
0.3%
75%
60%
0.1%
50%
33%
Time of maternal HIV testing among
infants with perinatally acquired HIV
US; birth years=2006–2009;
40 States, N=365
10%
14%
39%
Before pregnancy
During pregnancy
At birth
10%
After birth
Unknown
27%
Watts DH, et al. Contraception 2008;77:84–90.
How can we prevent this?
MOTHER-TO- CHILD
TRANSMISSION OF HIV
Perinatal HIV transmission
• In 1994, before standard AZT use: 21% transmission
• In 1995, immediately after recommended standard AZT
use: 11% transmission
• Today, risk can be <1–2% with:
–
–
–
–
Routine prenatal care
Effective ART
Availability of scheduled cesarean section (C/S) if needed
Formula feeding
Trends in reduction of MTCT:
Results over time in the field
35
30
% Transmission
25
20
15
10
5
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
USA and Europe
McIntyre J, et al 12th CROI 2005; #8
Thailand
Africa
Mother to child transmission in the UK and
Ireland – 2000–2006 (HAART era)
Total
HAART
Dual therapy
Monotherapy
None
Undetectable (<50
copies/ml)
50–999 copies/ml
1,000–9,999 copies/ml
At least 10,000 copies/ml
Missing
At least 500 cells/µl
350–499 cells/µl
200–349 cells/µl
Less than 200 cells/µl
n infected
MTCT rate (%)
Antiretroviral therapy (n=5027)
4120
40
126
1
638
3
143
13
Mode of delivery (n=5027)
HIV viral load (n=4096)
2309
3
1023
12
429
6
335
20
1035
20
CD4 cell count (n=3962)
1389
11
1011
11
1080
11
482
7
* Overall transmission rate in cohort 1.2%
Townsend CL, et al. AIDS 2008;22:973–981.
Crude OR
1
0.8
0.5
9.1
1
0.82
0.48
10.2
0.1
1.00
1.2
1.4
6.0
1.9
9.12
10.90
48.80
0.8
1.1
1.0
1.5
1.00
1.38
1.29
1.85
Factors associated with MTCT:
Factor
Number (%)
Acute HIV Infection during pregnancy
12 (26%)
No or inadequate care
14 (30%)
Non-adherent to ART
15 (32%)
Other (no prenatal test, late
diagnosis, etc)
6 (12%)
47 Infants with HIV Infection, NYS Jan 2002–Dec 2004
Birkhead G. XVI Internat AIDS Conf, 2006, Toronto Abs WePE 0271
Timing of transmission
Antenatal
Early
Late
Pregnancy
10–25%
<28 wks
Postpartum
>28 wks
Early
Late
Breast Feeding
35–40%
Labour and Delivery
35–40%
0–1 mo
1–6 mos
6–24 mos
Selected clinical risk factors for MTCT
• Obstetrical
– Duration of rupture of membranes (ROM)
– Invasive labor procedures
– Concomitant STDs, especially ulcerative, also Bacterial
vaginosis
– Chorioamnionitis
– Low birth weight
• HIV Disease
– Low CD4
– Viral load at the time of delivery
– Lack of antivirals
• Other: other infections (hepatitis, CMV), Illicit drug use
and cigarette smoking
% Transmission
HIV-RNA levels and ARV use are
associated with perinatal transmission
60
40
None
ZDV Mono (<4/94)
ZDV Mono (>4/94)
Multi-HAART
20
0
HAART
Increasing Maternal plasma HIV-1 RNA copies/mL
Cooper E, et al. JAIDS 2002;29:484–94.
Transmission according to last
antenatal VL: PACTG 367 (1998–2002)
Transmission Rate,
% (n)
95% CI
No RNA data
17.1% (39 / 228)
12.5–2.6%
10,000 or more
5.6%* (22 / 391)
3.6–8.4%
1,000 to 9,999
2.0%* (12 / 588)
1.1–3.5%
<1,000 or
undetectable
0.7%* (13 /1874)
0.4–1.2%
RNA, copies/ml
*>10,000 vs. 1,000-9,999 vs. <1,000 / undet.: P<0.001
Shapiro 11th CROI, San Francisco 2004, #99
Residual transmission in France,
1997–2007
• Case-control study in France: 19 cases (transmitters despite
antenatal VL on ART <500); 60 controls (non-transmitters
with same)
• Cases less likely to be on ART at conception (16% vs 45%)
• Viral load <500 copies/mL cases versus controls:
– 14 weeks: 0% vs 38.1%
– 28 weeks: 7.7% vs 62.1%
– 32 weeks: 21.4% vs 71.1%
• Multivariate analysis (VL, CD4+, timing of ART initiation): viral load
only factor independently associated with MTCT
• Earlier and sustained control of viral load is associated with a
decreasing “residual” risk of HIV MTCT
Tubiana R, et al. CID 2010;50:585–596.
Case report: Mrs BK
What would you recommend in terms
of her ARV?
She is currently on efavirenz and abacavir/3TC:
1. Switch the efavirenz to lopinavir/r
2. Switch the abacavir/3TC to AZT/3TC
3. Leave her current ARV as her viral load is
undetectable
4. Switch the efavirenz to nevirapine
5. Switch her to atripla
Case report: Mrs BK
• Efavirenz switched to LPV/r
• Continued on abacavir/3TC
• Initially considerable problems with gas and
diarrhoea
• Manipulated diet and timing of tablets with
improvement
Case report: Mrs BK
• May 2009: pregnant; EDC Jan 3, 2010
• Referred to obstetrics, screening ultrasound,
children’s hospital for counselling
• Increase in fatigue
• CD4 785 (34%), viral load <50/mL
• Added chronic suppressive therapy with
acyclovir for genital HSV
Perinatal guidelines
http://aidsinfo.nih.gov
Guidelines for ART in pregnancy:
General principals
• ART to decrease transmission regardless of HIV
parameters (VL, CD4)
• Combination therapy is standard of care both for
treatment and pMTCT
• Longer duration of ART is better for pMTCT than shorter
duration
• 3-part AZT should be included, unless there is significant
toxicity or resistance; IV AZT for all
Factors in choosing ART for pregnant
women
• Indication for therapy (maternal HIV disease, pMTCT)
• Goals and consideration as in non-pregnant patients: potency,
durability, preservation of future options, toxicity and tolerability,
resistance, adherence
• Pregnancy specific issues: efficacy in pMTCT, maternal & fetal
toxicity, teratogenicity, long-term toxicity, pK, transplacental transfer,
timing of treatment initiation, hyperemesis and nausea of pregnancy
• Choice often made based on collective experience and consensus
guidelines, rather than randomized trials
Placental transfer of antiviral drugs
(antivirals as PrEP and fetal toxicity)
• PrEP of infant from transplacental passage of drug is an
important component of prevention
• At least one NRTI with high placental transfer should be
used: ZDV, 3TC, d4T, ABC, FTC, TDF
• All NNRTIs cross the placenta
• There is minimal placental transfer of PIs (LPV
transferred better than others)
• Raltegravir likely crosses placenta
Safety of ART during pregnancy:
Antiretroviral Pregnancy Registry
• A collaborative project managed by PharmaResearch
Corporation on behalf of an advisory committee
(OB/GYN, teratology, epidemiology & ID specialists,
CDC, NIH) & sponsored by pharmaceutical companies
• Voluntary reporting
• Purpose: To assess safety of ARV drugs during
pregnancy
• Telephone: (800) 258-4263 Fax: (800) 800-1052
available at http://www.apregistry.com
FDA pregnancy categories
A Studies of pregnant women fail to demonstrate a risk to the fetus
during the first trimester of pregnancy
B Animal studies fail to demonstrate a risk to the fetus. Studies of
pregnant women have not been done
C Safety in human pregnancy has not been determined. Animal
studies are either positive for fetal risk or have not been conducted
D Evidence of human fetal risk. The benefits from the use of the drug
in pregnancy may be acceptable despite its risks
X Animal and /or human data indicate that the risk associated with the
use of the drug in pregnancy clearly outweighs any possible benefit
Birth defects associated with firsttrimester exposure to individual agents
Incidence (% live births)
6.0
4.7
5.0
4.0
3.0
2.5
3.0
2.8
3.8
2.8
3.1
2.45
2.0
1.0
0.0
CDC=Center for Disease Control; comparison to the general population
Antiretroviral Pregnancy Registry International Interim Report for 1 Jan
1989–31 July 2010. Jan 2011
2.5
2.1
2.72
Safety of efavirenz in first-trimester
observational cohorts
• Systemic review and meta-analysis of 16 studies found 9
prospective studies reporting on congenital abnormalities
in infants exposed to ART in first trimester
– 1,132 live birth exposed to efavirenz containing regimens
– 7,163 live birth exposed non-efavirenz containing ART
• Across all studies, one neural tube defect was reported
with efavirenz use
• No increased risk of overall birth defects was found
when efavirenz was compared with other antiviral drugs
• Study VERY SMALL
Ford N, et al. AIDS 2010;24:1461–70.
Perinatal ARVs and congenital
anomalies: P1025
• Outcomes of infants enrolled in IMPAACT P1025 and
born 2002–2007
• 61/1112 infants had congenital anomaly (5.49/100 live
births [95% CI: 4.22–6.99)]) – higher than general
population in 2008 (2.76/100 live births) and in WITS
(3.6), APR (2.9)
• Efavirenz exposure in 1st trimester demonstrated odd
ratio (OR) of 2.89 (95% CI: 1.15–7.25) for congenital
anomaly
Conway, CROI 2010 #923
Perinatal ARVs and congenital
anomalies: P1025
Association of timing of first in utero ARV exposure and congenital anomalies
Timing of first in utero ARV
exposure
Any
ARV
NRTI
NNRTI
PI
ZDV
EFV
Conway, CROI 2010 #923
Unexposed
1st trimester
2nd/3rd trimester
Unexposed
1st trimester
2nd/3rd trimester
Unexposed
1st trimester
2nd/3rd trimester
Unexposed
1st trimester
2nd/3rd trimester
Unexposed
1st trimester
2nd trimester
Unexposed
1st trimester
2ns trimester
Child has anomaly?
Yes
No
(n=61)
(n=1061)
0 (0.0%)
12 (1.1%)
33 (54.1%)
486 (46.3%)
28 (45.9%)
552 (52.6%)
1 (1.6%)
14 (1.3)
31 (50.8%)
478 (45.5%)
29 (47.5%)
558 (53.1%)
49 (80.3%)
856 (81.5%)
9 (14.8%)
120 (11.4%)
3 (4.9%)
74 (7.0%)
14 (23.0%)
293 (27.9%)
22 (36.1%)
324 (30.9%)
25 (41.0%)
433 (41.2%)
10 (16.4%)
177 (16.9%)
19 (31.1%)
336 (32.0%)
32 (52.5%)
537 (51.1%)
55 (90.2)
1000 (95.2%)
6 (9.8%)
41 (3.9%)
0 (0.0%)
9 (0.9%)
Odds ratio
(95% CI)*
Reference group
**
**
Reference group
0.94 (0.11, 8.10)
0.74 (0.09, 6.36)
Reference group
1.52 (0.72, 3.23)
0.77 (0.22, 2.70)
Reference group
1.30 (0.63, 2.67)
1.14 (0.57, 2.26)
Reference group
0.95 (0.42, 2.25)
1.05 (0.49, 2.24)
Reference group
2.89 (1.15, 7.25)
**
Birth defects of ATZ in pregnancy
• From pregnancy registry
• N=698; 604 recorded outcomes
• N=368 first trimester; eight birth defects, prevalence
2.2% (0.9–4.2%)
• Second/ third trimester exposure (n=199); five defects,
defect rate 2.5%
• No obvious pattern for defect
Esker, HIV10, abstract P113
Safety of ATZ/r in pregnancy
•
•
•
•
N=41 (n=20, 300/100mg; n=21 400/100mg)
Grade 3–4 bilirubin in mother: 6/20; 13/21
All infants had normal bilirubin at birth through day 14
Then seven developed grade 3–4 bilirubin consistent
with physiologic changes in normals
• Maternal bilirubin, cord ATZ levels poorly predictive of
infant bilirubin
McGrath, Abstract 019, Lipo 2010
Safety of ART in pregnancy PIs
• Hyperglycemia
• Theoretical concern for kernicterus: IDV and ATV
(indirect, protein binding)
• Controversial: premature birth, low birth weight – data
may be biased by indication for PI therapy
Preterm delivery rates by type of
antiretroviral therapy
25
20
15
No therapy
Monotherapy
10
Dual therapy
HAART
5
0
Pediatric Spectrum of European Collaborate National Study of HIV
HIV Disease Project
Study
Pregnancy and
Childhood
Townshead CL, et al. BJOG 2010;117:1399–1410
Effect of prenatal cARV exposure on
live births
Proportion of live births that had low birth weight or preterm delivery
following prenatal exposure to cARV with and without PI*
18%
Combination without PI
16%
Combination with PI
14%
Live Births
12%
Low birth rate risk ratio =
1.22, P<0.001;
preterm delivery risk ratio =
1.27, P<0.001
10%
8%
6%
4%
2%
0%
<2500g
<1500g
Birth Weight
<37 weeks
Estimated Gestational Age
cARV≥ 2 ARVs; * Singleton live birth outcomes without birth defects
Beckerman K, et al; Poster TULBPE018
<32 weeks
TDF in pregnancy
• Recommended in special circumstances (HBV, resistance, ZDV
intolerance)
• IMPAACT P1026s, tenofovir PKs: AUC lower. Troughs unchanged;
significance not clear. No dose adjustments
• Theoretical safety concerns: bone mineralization, and renal function
• Animal studies: reversible bone abnormalities in some; dose,
exposure, age, and species specific
• Case series of 76 women: well tolerated.
• In 20 TDF-exposed infants and 20 controls no differences in renal
function, including cystatin C levels, through to 2 years of age
• Retrospective review of 16 pregnancy outcomes in 15 heavily ARV
experienced women: normal growth and development in TDFexposed infants
Habert CROI 2008; Linde R CROI 2010;
Nurutdinova D, et al. Ann Pharmacother. 2008;42:1581–1585.
Mma Bana study, Botswana:
Birth outcomes
Arm A
(TZV)
Arm B
(KAL/CBV)
Stillbirths (% of deliveries)
8 (3%)
5 (2%)
Live births (including twins)
283
270
61 (23%)
Obs Arm
(NVP/CBV)
11 (7%)
(p=0.07 for randomized
versus observational arms)
156
Prematurity (< 37 weeks*)
42 (15%)
Low Birth Weight (< 2.5 kg)
37 (13%)
45 (17%)
23 (15%)
Congenital Abnormality
5 (2%)
5 (2%)
5 (3%)
Shapiro RL et al. NEJM 2010; 362:2282–2294.
(p=0.04 for
Arm A versus Arm B)
16 (10%)
In utero ARV exposure: Potentially
concerning toxicities
• Congenital anomalies (EFV, other?)
• Prematurity/low birth weight (PI)
• Abnormal fetal bone mineralization and growth (TDF)
• Hematologic abnormalities (NRTI)
• Mitochondrial dysfunction (NRTI)
• Increased malignancy risk1–3? (NRTI, through
mutagenesis, clastogenesis and telomere attrition)
• Cardiovascular abnormalities? (NRTI)
• Neurodevelopmental problems
1. Mandelbrot L, et al. AIDS 2008;22:2165–77; 2. Hankin C, et al. AIDS;21:867–9;
3. Brogly S, et al. JAIDS;41(4):535–6.
When to start: Treating before or after
organogenesis
• Treating Early
– Assess efficacy
– Assess tolerability
– Assess adherence
– Early and sustainable
virologic control 
lower residual
transmission
• Deferring to 2nd trimester
– Avoid fetal toxicity
– Delay treatment if
undesired and not
otherwise indicated
– Cost
Public Health Service Task Force
ARVs in pregnant HIV-infected women
Recommended
Alternate
Insufficient data/special
circumstances
NRTI
Lamivudine
Zidovudine
Abacavir
Didanosine
Emtricitabine
Stavudine
Tenofovir
NNRTI
Nevirapine
Efavirenz
Etravirine
Protease Inhibitors/Other
Lopinavir/r
Atazanavir/r
Indinavir/r
Saquinavir/r
Nelfinavir
Ritonavir
Darunavir/r
Tipranavir/r
Fosamprenavir/r
Raltegravir
Maraviroc
Public Health Service Task Force, Recommendations for Use of Antiretroviral Drugs
in Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce
Perinatal HIV Transmission in the United States, May 2010
Drug PK in pregnancy: Physiologic
changes affecting drug administration
• Cardiovascular: increased cardiac output,
volume expansion, changes in regional blood
flow  dilution
• Gastrointestinal: delayed gastric emptying,
increased gastric acidity, increased transit time
 absorption
• Renal: increased GFR 20–60%  clearance
• Hepatic: enzyme activity changes: CYP34A and
CYP2D6 increased, others decreased
 clearance
Case report: Mrs BK
What do you recommend around the
time of delivery?
1. She should have a caesarean section
2. You should increase her LPV/r dose
3. You should monitor her viral load and if it increases
then increase her LPV/r dose
4. She should receive intravenous AZT during labour
5. No changes, and allow a vaginal delivery
ARV PKs in pregnancy
NRTIs
Abacavir
Didanosine
Emtricitabine
Lamivudine
Stravudine
Zidovudine
NNRTIs
No ∆
No ∆
No ∆
No ∆
No ∆
No ∆
Nucleotides
Tenofovir
AUC?
Fusion inhibitors
Enfuvirtide
No data
CCR5 co-receptor
antagonists
Maraviroc
No data
Efavirenz
Etravirine
Nevirapine
No data
No data
No ∆
PIs
Atazanavir
AUC ↓
Darunavir
No data
Fosamprenavir AUC ↓
Indinavir
AUC ↓
Lopinavir/rit
AUC ↓
Nelfinavir
AUC ↓
Ritonavir
AUC ↓
Saquinavir
AUC ↓
Tipranavir
No data
Integrase inhibitors
Raltegravir
No data
Median (+SE) Lopinavir (mcg/mL)
Lopinavir concentrations with
400/100mg BID dose (PACTG 1026S)
10
9
Results in lopinavir
concentrations
during pregnancy
that are ~50% lower
than postpartum
8
7
6
5
4
3
What is important?
2
Free drug? Vs
total drug
1
0
0
1
2
3
4
5
6
7
8
9
10
Time Post Dose (hours)
Antepartum
A.Stek et al IAS 2004
Postpartum
11
12
13
LPV/r PK studies: Tablets
Author
Publication Country
N
PK
Results/Recommendations
Dose
KhuongJosses
CROI 2007
36
TDM
SD provide adequate levels of exposure even during the
T3 and viral suppression.
SD
Baroncelli
Ther Drug
Mon 2008
Italy
26
Sparse
SD provided adequate levels of exposure during T3 with
good viral suppression. None of newborns were infected
with HIV
SD
Kiser
CROI 2009
US
10
With SD LPV & RTV significantly less protein bound
Intensive during pregnancy vs. PP. 80% of subjects required
LPV/r dose ↑ in T2
HD
Best –
(IMPAACT
1026s)
JAIDS 2010
US
33
HD LPV/r (600/150mg) in T3 provided comparable levels
Intensive to SD in non-pregnant women. Recommends HD in T2
& T3 then SD in PP
HD
Cressey –
(IMPAACT
1032)
AIDS 2010
Thai
38
Intensive
SD LPV/r provided adequate LPV drug exposure in HIVinfected Thai women
SD
France
Lambert
HIV Med
2010
UK
46
Sparse
SD achieved above targeted conc in majority of
pregnant women but ↓ conc T2/T3 highlights need for
TDM. Recommends HD in T2 & T3
Taylor
IAS 2010
UK
11
Sparse
SD Reduced LPV conc in T2/T3 highlights need for TDM
SD+
TDM
Lyons
BHIVA & BA
STD 2010
P10
UK
9
Sparse
SD LPV/r, total LPV conc in excess of the IC50 for WT &
viral load undetectable in all plasma & genital tract
samples. All 9 infants HIV-1 uninfected
SD
Patterson
CROI 2011
US
12
SD achieved adequate levels in ARV naïve pregnant
Intensive women. Addition of pediatric LPV/r tab (100/25) in
women with resistance mutations in T2 may be sufficient
SD=standard dose; HD=high dose; T=Trimester; conc=concentration, PP=post partum
SD+
TDM HD
SD in
ARV
naive
Atazanavir in pregnancy
• IMPAACT (pACTG) 1026s:
– In 3rd trimester AUC below target in 33% w/o and
55% on TDF
– Trough concentration was below the target in 6%
(1 of 18)
– A dose increase to 400 mg/100 mg may be necessary
in pregnant women, especially if on TDF
Hardy. results of study AI424182. 1st International Workshop HIV & Women. DC 2011;
Mirochnick M, et. JAIDS 2011;56:412–419.
PK of atazanavir in pregnancy
• N=17 Italian pregnant women
on ATV+RTV with AZT+3TC
• Intensive 24 hour PK
performed in T3 and 8-16
weeks post-partum
• ATV overall exposure at
steady state during T3 similar
to pre-partum
• 17/17 women VL<50
• All infants HIV negative at 3
months
Ripamonti D, et al, AIDS 2007, 21:2409–2415.
Geometric least-squares mean atazanavir
concentration-time curves, with bar indicating
95% confidence intervals, during the third
trimester (▴) and postpartum (•)
Atazanavir pharmacokinetics with and
without tenofovir during pregnancy
• pACTG 1026s: Intense PK in 3rd trimester and 6–12 wks postpartum
in women taking ATV/RTV 300/100 QD with (20) or without (18) TDF
• Median atazanavir C24 h significantly ↓ during 3rd trimester compared
with postpartum both for women not receiving TDF (0.7 vs. 1.2
mcg/mL, P = 0.002) and those receiving TDF (0.5 vs. 0.8 mcg/mL, P
= 0.0008)
– AUC below target in 33% of women not receiving TDF and 55%
receiving TDF
• Ctrough below the target (0.15 mcg/mL) in 6% without TDF and 15%
receiving TDF
• Author’s Conclusion: Dose ↑ of ATV/RTV to 400 mg/100 mg may be
necessary in pregnant women to ensure ATV exposure equivalent to
non-pregnant adults
Mirochnick M, et al, JAIDS 2011;56:412–419.
Atazanavir pharmacokinetics with and
without tenofovir during pregnancy
Atazanavir without tenofovir
Mirochnick M, et al, JAIDS 2011;56:412–419.
Atazanavir with tenofovir
Case report: Mrs BK
What do you recommend
after delivery?
1.
2.
3.
4.
Stop all ARV as her CD4 count is > 500
Switch the LPV/r back to efavirenz
Continue the current regimen
Allow her to breast feed as her viral load is
undetectable and she is unlikely to transmit
5. Do not recommend contraception as she will not
likely get pregnant in the near future
Caesarean section and HIV
transmission
Vaginal delivery
(10.2%)1
Vaginal delivery + ZDV
(6.6%)2
Elective C section
(3.4%)
Elective C section + ZDV
(0.8%)
1. European Mode of Delivery Collaboration Lancet 1999;353:1035–1039;
2. Mandelbrot L et al. JAMA 1998;280:55–60.
MTCT in the UK and Ireland
2000–2006 (HAART era)
• Among 2117 infants born to women on HAART, with VL
< 50, only three (0.1%) were infected, two with evidence
of in-utero transmission
• Longer duration of HAART was associated with reduced
transmission after adjusting for VL, mode of delivery and
sex (adjusted odds ratio 0.90, or 10% reduction, per
week of HAART (P=0.007)
• Among women on HAART, there was no difference in
MTCT rates between elective CS (0.7%, 17/2286) and
planned vaginal delivery (0.7%, 4/559); adjusted for sex
and viral load
Townsend CL, et al. AIDS 2008;22:973–981.
Case report: Mrs BK
Would you recommend a C-section if
she also had HCV?
1. Yes
2. No
3. Depends on her HCV viral load
Can I breast feed?
•
•
•
•
Complete avoidance of breastfeeding is efficacious in pMTCT of HIV
Formula milk also has disadvantages
Discrimination/stigma of not breastfeeding in some communities
If breastfeeding is initiated, three interventions to be considered
– Continuing ART for the mother following delivery
– Chronic ART prophylaxis for the infant (nevirapine alone, or
nevirapine with zidovudine)
– Limiting breastfeeding to the first few months of life
The concerns
• HIV transmission (HIV-DNA in milk of women with undetectable VL)
• ART passed through milk to child with unknown long-term effects
Mma Bana study
•
•
A Randomized Trial Comparing Highly Active Antiretroviral Therapy
Regimens for Virologic Efficacy and the Prevention of Mother-to-Child HIV
Transmission among Breastfeeding Women in Botswana
Primary outcomes:
–
Maternal HIV-1 RNA < 400 copies/mL at delivery & throughout breastfeeding at 1, 3, 6M (or weaning)
–
MTCT rates by infant HIV DNA PCR at birth and 1, 3, 6 months
TZV
(Arm A) n=285
M1
M3
M6
CD4 > 200 cells
24-36 W
LPV/r
400/100+ CBV
M1
(Arm B) n=275
Observational arm: <200 CD4
NVP 200mg + CBV (18 - 34W) n=170
Shapiro R: 1st HIV International Peds Wkshp;July 2009; MO-940
M3
M6
Mma Bana study
• 730 women enrolled: 560 randomized (PI vs NRTI); 170
observational (Obs)
• HIV-1 RNA suppression did not differ by randomization
arm at birth (93% PI vs 96% NRTI; p=0.18), or
throughout breastfeeding (93% PI vs 92% NRTI; p=0.98)
and Obs 95%
• MTCT rates were low: <1% in PI (one in utero
transmission) vs 2% NRTI (three in utero and two
breastfeeding); p=0.53 and <1% Obs (one in utero)
• Infant 6-month mortality was 3% PI; 2% NRTI and
Obs 4%
Shapiro R, et al. N Engl J Med 2010;362:2282–94.
Mma Bana study
Shapiro R et al. N Engl J Med 2010;362:2282-94
BAN study (Breastfeeding, Antiretroviral and
Nutrition): 28-week results
Mothers CD4 >250 cells (36GA)
iBW > 2000 gms
IP SD NVP to both
+ 1W AZT+3TC
LPV/r + CBV + MNS
iNVP + MNS
No ARV + MNS
vs.
vs.
vs.
LPV/r + CBV & no MNS
iNVP & no MNS
No ARV & no MNS
n=800
n=800
n=800
• Mothers breastfed exclusively for 24 weeks followed by rapid weaning
• Kaplan-Meier method was used to estimate the cumulative risk of HIV infection or
death at 28 weeks among infants who were HIV-1 free 1 week after birth
• Rates were compared using the log-rank test, stratified by nutritional supplement
iBW=infant Body Weight; MNS=Maternal Nutritional Support; iNVP=infant NV; mHAART=maternal HAART
Chasela C, NEJM 2010; 362:2271–81.
BAN study: Results
• By Week 2 after delivery, infants in each three study groups had
similar estimated risk of infection: 5.4% control group, 5.5%
maternal-regimen group, & 4.4% infant-regimen group (p=0.35)
• Estimated risk of HIV-1 transmission by 28 weeks in those
uninfected at week 2 was higher in control arm (5.7%) compared to
either intervention arms (2.9% in maternal HAART [p=0.003] and
1.7% in infant NVP arm [p<0.0001])
• Estimated risk of HIV-1 transmission or death by 28 weeks was
7.0% in control arm compared to 4.1% in maternal HAART arm
(p=0.03) & 2.6% in infant NVP arm (p<0.0001)
• Conclusion: Either maternal HAART or infant NVP for 28 weeks is
effective in reducing HIV-1 transmission during breastfeeding
Chasela C, et al. NEJM 2010; 362:2271–81.
BAN study: Results
Probability of infant HIV-1 infection or death by 28 weeks
Chasela C, et al. NEJM 2010;362:2271–81.
Is it SMART to stop after pregnancy?
• SMART study suggests that stopping results in
increased HIV-related and unrelated clinical events
regardless of CD4
• Want a healthy mother
• What about transmission to a non-discordant partner
Stopping ART post-partum
• Controversial issue
• If Nadir CD4 falls within guidelines to treat – continue,
but most would recommend continuing in all in resource
rich settings, as treatment interruption not recommended
in other settings
• If discontinued, stop all drugs simultaneously, unless
significant differences in half-life
• Modifications appropriate
• Do not stop in HBV co-infected (reactivation risk)
• Contraception, contraception, contraception
• Adherence monitoring
PROMISE – P1077 study: Promoting
maternal infant survival everywhere
PMTCT 3rd trimester
N = 4400
n = 3100
PMTCT Breastfeeding
N = 4650
n = 3950
Maternal Health
N = 5950
(Developing world)
(Developing world)
(Global)
Compare efficacy and
safety of LPV/r-based
HAART initiated during
third trimester vs.
standard of care for
PMTCT
Compare efficacy and
safety of maternal LPV/rbased HAART vs. daily
infant NVP prophylaxis for
PMTCT throughout
breastfeeding
Assess clinical benefit and
safety of long term LPV/r
based HAART vs. therapy
cessation post PMTCT
LPV/r HAART
LPV/r HAART
LPV/r HAART
vs.
vs.
vs.
Infant NVP
Stop
All ARVs
AZT
AZT +
SD NVP+
7d TRV
Case report: Mrs BK
• Spontaneous vaginal delivery
• Baby HIV-negative
• Discussed continuing current ARV or switching back
to EFV
• She preferred LPV/r as she had fewer CNS symptoms
• Feb 2011: all well, returned to work
• Jan 2011: CD4 > 700/mm3, VL<50/ml
Case report: Mrs BK
• Generally well
• Struggles with fatigue and occasional
sleeplessness
• Some nausea with medications – infrequently
misses doses
• 2008: CD4 470 (28%), and viral load <50
copies/ml
Conclusions
• Given the improvements in morbidity and
mortality and the changing epidemiology of HIV
more women are electing to become pregnant
• Preconception counseling should occur early
and continuously as part of care for women
• Important considerations are maternal health,
prevention of transmission to partners and
babies, drug interactions, ARV safety and
efficacy